Malaria is one of the most prevalent infectious diseases worldwide and it represents a major global health issue for which new effective chemotherapies are urgently needed. The most successful antimalarial drug for decades was chloroquine, but the widespread emergence of resistant parasites in most endemic areas severely limits its efficacy. First- line antimalarial treatments today are based on artemisinin and related 1, 2, 4-trioxanes; these drugs are highly active and fast acting against chloroquine-resistant malaria, but they are limited by their short plasma half-lives, which results in parasite recrudescence when used as a monotherapy. The World Health Organization currently recommends combination therapies composed of artemisinin and amodiaquine, lumefantrine or mefloquine. Nevertheless, such combinations suffer from problems related to differences in solubility and pharmacokinetics of the individual components, which may compromise the ability of the trioxanes to prevent emergence of drug resistance; therefore new effective antimalarial therapies are needed. Our long-term goal is to discover and develop novel metal-based antimalarial chemotherapeutic agents for the treatment of human disease. Our objective in this proposal is to identify new lead compounds toward ruthenium-derived drugs for the treatment of malaria and to elucidate their mechanisms of action. Our central hypothesis is that combining ruthenium with chloroquine, a trioxane, or chloroquine and a trioxane in a single molecule will lead to new multifunctional compounds effective for specific targets in resistant malaria parasites, as a result of the physicochemical characteristics of the organometallic structure. This research is based upon our previous work and data from other researchers, strongly indicating that metal-based approach is a promising alternative for the development of non-toxic chemotherapeutic agents against resistant malaria. The specific aims of the project are: 1. to synthesize and evaluate the antimalarial potential and toxicity of covalently linked Ru-chloroquine complexes targeting heme aggregation. 2. To synthesize and evaluate Ru-trioxane and Ru-(bis) trioxane complexes as potential non-toxic antimalarial agents acting by radical alkylation mechanisms. 3. To synthesize and evaluate hybrid Ru-chloroquine-trioxane complexes as potential non-toxic antimalarial agents acting by dual mechanisms. PUBLIC HEALTH RELEVANCE: Malaria is one of the most prevalent infectious diseases worldwide; 300-500 million people become infected and close to a million die of malaria each year, mostly children under 5 years of age. The most important issue in the treatment of malaria today is the widespread emergence of resistance to commonly used drugs. This proposal presents a promising alternative toward the development of novel and effective metal-based antimalarial therapies and it opens important avenues of research for understanding their mechanisms of action.